The value of fine-needle aspiration biopsy wash-out fluid in the detection for medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is characterized by a high concentration of serum calcitonin. Routine measurement of serum calcitonin concentration has been advocated for detection of MTC among patients with nodular thyroid diseases. However, a minimal to moderate increase of serum calcitonin concentration has been frequently observed in diseases other than MTC. Fine-needle aspiration cytology (FNAC) is not a reliable method for detection of MTC. Therefore, we evaluated the usefulness of routine measurement of serum calcitonin concentration in patients with nodular thyroid diseases, and studied the validity of pentagastrin stimulation test and FNAC in these patients. We performed routine measurement of serum calcitonin concentrations in 1,448 patients (male, 285, female, 1,163) with nodular thyroid diseases. The average age was 46 years (range, 14-86 years). Initial examination included thyroid examination, thyroid scan or ultrasonography, measurements of serum free triiodothyronine) (T3), free thyroxine (T4), thyrotropin (TSH) levels, and antithyroid autoantibodies. FNAC was performed in all patients who had palpable or visible thyroid nodule by ultrasonography, and pentagastrin stimulation test was performed in 39 patients who consented. Serum calcitonin concentration was measured with a two-site immunoradiometric assay using commercial kits. We also measured the serum calcitonin concentration in 407 healthy subjects without thyroid or nonthyroid diseases. Serum calcitonin concentration was 10 pg/mL or less in 403 normal subjects (99.0 percentile), and 11-13 pg/mL in the remaining 4 subjects. We found that 56 (3.87%) of 1,448 patients with nodular thyroid diseases had serum calcitonin level above 10 pg/mL. Ten patients (0.69%) with histologically confirmed MTC were detected by the routine measurement of serum calcitonin. The prevalence of MTC was 5.2% in 194 patients with thyroid carcinoma. Five of 10 patients with MTC had basal serum calcitonin level above 100 pg/mL. The remaining 5 patients had minimal or moderate elevation of basal serum calcitonin (range, 12-86 pg/mL). Serum calcitonin concentration increased to more than 100 pg/mL by pentagastrin in all patients with MTC (2.4- to 37.7-fold increase). FNAC suggested MTC in only 2 patients (22.2%), and failed to diagnose MTC in 7 patients. FNAC was not performed in 1 patient with MTC, because he had no visible mass by ultrasonography. These results suggested that routine measurement of serum calcitonin is useful in the early detection of MTC among patients with nodular thyroid diseases. Pentagastrin stimulation test may also be a reliable way for evaluating thyroid nodular patients with mild or moderate elevation of serum calcitonin concentrations. However, FNAC was not sensitive in detecting MTC. We recommend routine measurement of serum calcitonin concentration in patients with nodular thyroid diseases.

Calcitonin measurement in washout of the needle after aspiration (WO-Ct) has been rarely evaluated. Here we analyzed the role of WO-Ct in a series of subjects who underwent fine needle aspiration (FNA) with suspicious medullary thyroid cancer (MTC). Twenty-one patients referred following elevated serum calcitonin (S-Ct) or suspicious MTC by cytology. All patients underwent re-evaluation of S-Ct, FNA, and measurement of WO-Ct. S-Ct and WO-Ct were assessed by chemiluminescence assay (IMMULITE 2000, Diagnostic Products Corporation, USA). S-Ct showed elevated value in six subjects (mean 368.8 ± 373.9 pg/ml), of which three cases were cytologically classified as Class 5. WO-Ct obtained in this group (304.0 ± 309.3 pg/ml) was no different from S-Ct. After surgery MTC was confirmed in all patients. In the other 15 patients MTC was excluded by cytology or histology. Two subjects had moderately skewed S-Ct with nonmedullary histology. In the remaining 13 patients S-Ct resulted normal (6.2 ± 5.6 pg/ml) and WO-Ct low (2.9 ± 2.2 pg/ml). Significant (two-tailed P < 0.05, r(2) = 0.27, 95% confidence interval = 0.017-0.81) correlation was found between S-Ct and WO-Ct in nonmedullary patients but not in MTC patients. This study showed that WO-Ct can play a role in diagnosing primary and metastatic MTC. The procedure is easy, cost effective, and should be used in patients undergoing FNA with elevated S-Ct. Further studies and guidelines for the method are needed to use this technique in clinical routine. Until this any institute should use itself cut-off.

The prevalence of sporadic forms of medullary thyroid carcinoma (MTC) has been studied in patients living in an area of moderate iodine deficiency. Such forms of MTC are usually diagnosed after surgery and have little chance of definitive cure. Using the measurement of basal serum calcitonin (CT) levels in a large series of patients with both thyroid disease and normal 24-hour urinary iodine excretion, we assessed the prevalence of MTC and, in patients affected with the disease, we also evaluated the stage of the disease according to surgical findings and post surgical plasma CT levels. A prospective study of 657 patients with thyroid disease (469 with nodular and 188 with non-nodular thyroid disease). As controls, 40 normal subjects were also studied. In all patients: (1) measurement of basal serum CT, free T4, total T3, TSH levels and serum TSH-receptor, peroxidase and thyroglobulin (Tg) antibody concentrations, (2) thyroid ultrasonography, (3) fine needle aspiration cytology (FNAC). In patients with increased basal CT levels: (1) measurement of serum CT levels during pentagastrin test prior to surgery, (2) histological examination and immunostaining with both anti-CT and anti-Tg antibodies of all the nodular thyroid tissue surgically removed, (3) measurement of basal and pentagastrin stimulated serum CT values after surgery. All the patients with non-nodular thyroid disease had normal basal CT levels. Four patients (0.84%) with nodular thyroid disease (2 with uninodular and 2 with multinodular goitre) had both elevated basal and pentagastrin stimulated CT levels. In the two patients with uninodular goitre, FNAC was suggestive of MTC in 1 (nodular diameter 8.0 cm) and of follicular carcinoma in 1 (nodular diameter 2.5 cm). Histological examination of the nodules confirmed these histotypes. Immunostaining with anti-CT antibodies was positive in the former patient but also in the latter. FNAC was suggestive of benign adenomatous tissues in the two patients with multinodular goitre. Histological examination of all the thyroid nodules confirmed the cytological findings. However, serial sections through the gland in each of these two patients showed an occult follicular carcinoma which had, however, positive staining with anti-CT antibodies. Furthermore, immunostaining with anti-Tg antibodies was negative in the patient with MTC but positive in the 3 patients with follicular carcinoma. Finally, both basal and pentagastrin stimulated CT levels remained elevated after total thyroidectomy only in the patient with FNAC suggesting MTC. This study demonstrates a surprisingly high prevalence of sporadic forms of medullary thyroid carcinoma in patients with nodular thyroid disease. Such forms of medullary thyroid carcinoma seem to be unrelated to iodine intake and may be pure or mixed with a follicular carcinoma. In these mixed thyroid carcinomas, only the neoplastic follicular pattern was seen on both cytological and histological examination. Routine measurements of serum calcitonin levels should therefore be considered an integral part of the diagnostic evaluation of thyroid nodules. Indeed, increasing the accuracy of diagnosis of medullary thyroid carcinoma encourages the surgeon to perform more radical treatment, thus achieving more frequent normalization of post-operative serum calcitonin levels.

Routine measurement of serum calcitonin to detect medullary thyroid carcinoma (MTC) continues to be fiercely debated, although less attention has been paid to the positive predictive value (PPV) of this method. We collected data from 959 patients with nontoxic nodular goiter; thyroidectomy was performed in 307 of these patients. Thirty-nine patients had elevated serum calcitonin; 6 of these patients had MTC detected by the initial diagnostic setup. No additional patient in the cohort was registered in the Danish Thyroid Cancer Database, reflecting that all patients with MTC were classified correctly initially. The sensitivity of serum calcitonin for detection of MTC was 100%, the specificity was 95.3%, the positive predictive value was 15.4%, and the negative predictive value was 100%. Serum calcitonin has high sensitivity and specificity for detection of MTC. The low PPV might lead to unnecessary thyroid surgery. Thus, the result of serum calcitonin measurement should always be interpreted in the context of other clinical variables.

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.

To assess whether routine measurement of serum calcitonin (CT) could improve the preoperative diagnosis of sporadic medullary thyroid carcinoma (MTC), 1385 consecutive patients presenting for nodular thyroid disease during the year 1991 were submitted to serum CT determination and fine needle aspiration cytology (FNAC). The clinical diagnosis was nontoxic nodular goiter in 1197 (86.4%) patients, toxic multinodular goiter in 65 (4.7%), autonomously functioning thyroid nodule (AFTN) in 64 (4.6%), and autoimmune thyroid disease (Graves' disease or Hashimoto's thyroiditis) with nodule(s) in 59 (4.3%). As controls, 177 patients with nonnodular thyroid disease and 32 normal subjects were also studied. Patients with FNAC suspicious of any kind of thyroid carcinoma and patients with elevated basal and pentagastrin-stimulated serum CT, regardless of the results of FNAC, were submitted to surgery. Eight (0.57%) patients (7 with nontoxic nodular goiter and 1 with AFTN) had elevated basal serum CT levels, ranging between 55-10,000 pg/mL. The pentagastrin test was abnormal in all of them. FNAC was suggestive of MTC in 2, thyroid carcinoma in 1, benign nodule in 3, and inadequate in 2. By histology, immunohistochemistry, and Northern blot analysis of total tumor RNAs, MTC was confirmed in all patients, including the 1 with AFTN, who had the association of microfollicular adenoma and a small MTC in the same lobe. After surgery, serum CT decreased to undetectable levels in 7 patients and remained undetectable in 6 of them during a mean follow-up of 22 months, although 1 of them had a positive response to pentagastrin. Forty-four patients in the group with normal serum CT levels had FNAC suspicious for differentiated thyroid carcinoma and were treated by surgery. Differentiated thyroid carcinoma, mostly papillary, was confirmed at histology in 43 subjects (3.1% of all thyroid nodules). In conclusion, the results of our study indicate that serum CT measurement is useful for the screening of sporadic MTC in patients with thyroid nodule(s). The prevalence of MTC, diagnosed by serum CT measurement in a 12-month period, among an unselected series of 1385 patients with nodular thyroid disease was surprisingly high: 0.57% of all thyroid nodules and 15.7% of all thyroid carcinomas. Serum CT measurement was superior to FNAC in suggesting the diagnosis of MTC and was devoid of falsely positive results. Increasing the diagnostic accuracy helped the surgeon to perform more radical treatment of MTC, thus achieving frequent normalization of postoperative serum CT levels. Whether this result indicates definitive cure remains to be established on the basis of longer follow-up.(ABSTRACT TRUNCATED AT 400 WORDS)

ABSTRACTObjective:To verify the cytopathological Bethesda System classification of thyroid nodule fine-needle aspiration biopsy (FNAB) in MTC patients and to assess the role of preoperative serum calcitonin (CT) levels in the investigation of this neoplasm in medullary thyroid cancer (MTC) patients under observation at the Uopeccan (União Oeste Paranaense de Estudos e Combate ao Câncer).Materials and methods:This is a cross-sectional review of medical records of patients monitored at the thyroid cancer outpatient clinic of Uopeccan. Clinical and demographic data, laboratory tests, ultrasound images, and cytopathological findings of MTC patients were evaluated.Results and discussion:Among the 360 patients with thyroid cancer monitored in the outpatient clinic, 5.2% (n: 19/360) had MTC. The hereditary form was more prevalent (63.2%), and there was no sex preference. The most common ultrasound findings were hypoechogenicity, solid appearance and microcalcifications. The FNAB diagnoses showed a sensitivity of 47.1%, and the most common cytopathological report was Bethesda category III. Serum CT levels showed good sensitivity (84.6%) for the diagnosis of MTC, and sensitivity levels were directly associated with the size of the nodule and distant metastases.Conclusion:Bethesda category III was more prevalent in this group of MTC patients. Serum CT levels were more sensitive than cytopathology for diagnosis of this neoplasm and were able to identify all patients who could not be diagnosed by FNAB.

Among various substances produced by C-cells, the most important one is calcitonin (CT) that is used for detection, post-operative follow-up and evaluation of individuals at risk of developing medullary thyroid carcinoma (MTC). However, the role of serum CT measurement in the evaluation of thyroid nodules has been widely discussed, and there is still no consensus about the role of CT in the initial evaluation of all thyroid nodules. Two patients with thyroid nodules whose fine-needle aspiration results were compatible with benign cytology besides having mildly elevated basal serum calcitonin levels were reported. Calcitonin responses (peak levels were 313 and 229 pg/mL, respectively) to calcium stimulation test were compatible with the possible diagnosis of MTC. However, the final diagnosis was papillary thyroid carcinoma of the thyroid gland. There are limited numbers of case reports showing such an increased serum calcitonin responses to calcium stimulation test associated with papillary or follicular thyroid carcinoma of the thyroid. We suggest to measure serum CT level once and in case of normal levels, no further CT measurement is necessary. Physicians should keep in mind that thyroid carcinomas other than MTCs may also be associated with high serum CT levels.Learning points:Although serum calcitonin is a valuable tumor marker for MTC, it is well known that mild elevations may be seen in some other diseases such as Hashimoto thyroiditis, neuroendocrine tumors or due to medications such as proton pump inhibitors, calcium salts, beta blockers and glucocorticoids.Those two cases indicate that high calcitonin responses to calcium stimulation test, mimicking MTC, may also be seen in patients with papillary thyroid carcinoma although the mechanism is not clear.

Many authors recommend the measurement of serum calcitonin (Ctn) to screen for sporadic medullary thyroid carcinoma (MTC) in patients with thyroid nodules. In this situation, procalcitonin (pro-Ctn) would have greater utility in patients with hypercalcitoninemia<100 pg/ml. The aim of this study was to evaluate the utility of pro-Ctn in patients with thyroid nodules and without a suspicion of familial MTC or type 2 multiple endocrine neoplasia who had mild or moderate hypercalcitoninemia without an apparent cause. Consecutive patients with nodular thyroid disease assessed routinely by Ctn measurement were selected. Sixty patients with basal Ctn>10 pg/ml but<100 pg/ml were included. Nine patients (15%) had MTC, with cytology being diagnostic in only four. Among the 51 patients without MTC, pro-Ctn was<0.1 ng/ml in 46 (90.2%). All patients with MTC had pro-Ctn>0.1 ng/ml. Basal Ctn was>24.6 pg/ml in all patients with MTC and in 42 patients (82.3%) without MTC. It is noteworthy that among patients with basal Ctn>24.6 pg/ml (n=18) pro-Ctn>0.1 ng/ml identified all patients with MTC and 64.2% of subjects with these pro-Ctn concentrations had this tumor. In conclusion, we did not find superiority of pro-Ctn over Ctn for the diagnosis of sporadic MTC in patients with nodular disease and mild or moderate hypercalcitoninemia. However, in the case of patients with hypercalcitoninemia in the gray zone, pro-Ctn has an excellent negative predictive value while the data regarding its positive predictive value are not uniform.

Thyroid cancer occurred in approximately 45,000 patients, in the USA in 2010. There is a 3:1 ratio of women to men. Histologic types are divided into categories of differentiated thyroid cancer (DTC): papillary, mixed papillary and follicular, and follicular—including Hurthle cell variant, undifferentiated (anaplastic), and medullary cancer (arising from parafollicular C-cells). Other rare thyroid carcinoma accounts non-epithelial tumors, lymphoma and carcinomas characterized by the presence of mucin-producing cells and keratin. Differentiated thyroid cancer usually presents as a thyroid nodule. Thyroid ultrasonography is useful to detect and characterize thyroid nodules, as well as guide fine needle aspiration (FNA) biopsy. Radioiodide or 99mTc-pertechnetate thyroid scan has a low diagnostic specificity and sensitivity for characterizing thyroid nodules. X-ray of the neck is useful to disclose a deviation of the trachea or lumen restriction, in large nodules and in multinodular goiter. CT or MRI are generally reserved for mediastinal thyroid masses, or the identification of regional or distant metastasis. The most widely used staging system for thyroid carcinoma is the TNM classification system defined jointly by the UICC and by AJCC. 131I-iodide thyroid remnant ablation is indicated in differentiated thyroid cancer patients with a moderate to high likelihood of recurrence. 131I-iodide therapy is usually administered in the amount of 1.85 to 3.7 GBq for ablation. Patients are prepared with rhTSH and low iodine diet. Whole body scan (preferably with SPECT/CT of the neck) is performed 4–7 days after radioiodine therapy to detect lymph node involvement or unexpected metastases. The major diagnostic modalities employed to follow patients with differentiated thyroid cancer treated with remnant ablation is measurement of serum Tg, 131I-WBS, and neck US examination. Neck US examination is an integral component of follow-up evaluation in all DTC patients. If a lymph node metastasis is suspected, an FNA should be performed. Serum Tg levels that become detectable upon TSH stimulation indicate the need for further evaluation, possibly with additional radioiodine therapy. Although CT and MRI can in principle localize very small lesions in the neck, chest, and bones, the features of such lesions are rarely specific for recurrent/metastatic DTC. Patients with recurrent thyroid cancer may develop lesions which cannot concentrate radioiodide. [18F]FDG PET/CT is useful in these patients to determine the sites and extent of these metastases. The anaplastic thyroid carcinoma (ATC) is a rare tumor (<3% of all thyroid cancers) with poor prognosis derived from follicular cells. The most clinical presentation of an ATC is a new, large, firm thyroid nodule, often associated with signs/symptoms of local compression/invasion. Multimodality treatment of ATC includes surgery, EBRT, and combination chemotherapy. Therapy with 131I-iodide is not useful, since these tumors rarely concentrate radioiodide. Preoperative imaging with US, CT, MRI play an important role, and [18F]FDG PET is useful. Medullary thyroid carcinoma (MTC) is a well-differentiated thyroid tumor arising from the parafollicular, calcitonin-producing C cells. Its prevalence is 5–10% in all thyroid malignancies. Sporadic and familial forms are recognized. Elevated baseline serum levels of calcitonin (above 10 ng/mL) are diagnostic for MTC. Following surgery, MTC patients are monitored with serum calcitonin and CEA levels, and serial neck US examinations are performed. Calcitonin doubling time in serum is the most sensitive biomarker for MTC progression. Scintigraphy with 123I-MIBG has very high sensitivity for staging patients with MEN II and familial MTC. However, it has a low sensitivity in patients with increased serum calcitonin but no clinical site of disease. [18F]FDG PET is accurate in detecting lymph node involvement. Radionuclide therapy with the radiolabeled somatostatin analog 90Y-DOTA-Tyr3-octreotide (90Y-DOTA-TOC) has been tested in metastatic MTC. Parathyroid carcinoma is a very rare endocrine malignancy that occurs in <1% of primary HPTH. The initial clinical manifestations of parathyroid carcinoma are primarily linked to the effects of markedly elevated serum PTH levels. At initial presentation, very few patients have metastasis at regional lymph nodes or at distant sites. Parathyroid carcinoma tends to infiltrate adjacent structures in the neck. US, CT, and MRI have been used to localize parathyroid carcinomas and to detect mediastinal and thoracic recurrences or distant metastases. 99mTc-Sestamibi scintigraphy can be successful for preoperative localization of the neoplasia and can identify metastases in lymph nodes and at distant sites. PET with [18F]FDG can also detect metastatic parathyroid cancers. Parathyroid carcinoma recurs in more than 50% of the cases and imaging studies should be performed in all patients before reoperation.

The prognostic value of serum calcitonin (CT) and carcinoembryonic antigen (CEA) doubling time has been recently demonstrated in medullary thyroid carcinoma (MTC) patients. No study has yet validated the surrogate role of these markers for survival during treatment. The aim of this study was to evaluate, in patients with advanced MTC treated with cytotoxic chemotherapy, the relationship between early changes of serum CT or CEA levels and progression-free survival (PFS). The files of 28 consecutive metastatic MTC patients with progressive disease, treated with cytotoxic chemotherapy in a single tertiary referral center between 2000 and 2010, were retrospectively reviewed. Serum CT and CEA measurements and radiological Response Evaluation Criteria in Solid Tumors (RECIST) evaluations were collected every 3 months. The relationship between changes in serum CT and CEA levels at 3 months, defined by an increase or a decrease of at least 20%, and PFS according to RECIST 1.0, was estimated using Kaplan-Meier curves and log-rank test. The median follow-up for the 28 patients was 68 months. According to RECIST, a partial response, a stabilization or a progression was observed in 14, 43, and 43% of cases respectively. Median PFS from the initiation of cytotoxic chemotherapy was 4.5 months. Median PFS among patients with and without significant CT increase at 3 months was 4.6 and 3.3 months respectively (P=0.75). Median PFS among patients with a significant CEA increase at 3 months was 2.7 months, whereas it was 19.1 months in patients in whom CEA did not increase (P=0.02). At 3 months, an increase of serum CEA but not of CT levels appears as a valuable surrogate marker of short PFS in MTC patients treated with cytotoxic chemotherapy. A prospective validation is expected.

Background Medullary thyroid carcinoma (MTC) has limited systemic options in advanced stages. Cancer-associated fibroblasts in tumor stroma in MTC overexpress fibroblast activation protein (FAP). FAP-targeted radioligand therapy (FAPI RLT) thus offers a novel theranostic approach. Alfa particle emitters like 225Actinium (225Ac) deliver high linear energy transfer (LET) to small, aggressive lesions, potentially improving tumor kill, where as bulkier lesions merit use of beta emitter 177lutetium alone or in tandem with 225Actinium. Methods A retrospective analysis of 31 patients with advanced/metastatic MTC treated FAPI RLT at our center was done. These patients had progressive disease despite exhausting TKI options. Pre therapy 68Ga-FAPI PET/CT demonstrated intense uptake in the lesions. 225Ac-FAPi (DOTAGA.Glu.(FAPi)_2) was administered intravenously (3.5–7.0 MBq (95–190 μCi) per treatment cycle) every 8 to 12 weeks. Patients with bulky disease received tandem therapy (two cycles of 177Lu-FAPi dimer ∼5–6 GBq of 177Lu-FAPi each followed by one cycle of 225Ac-FAPi dimer, with each cycle ∼8 weeks apart). Full blood count, renal, and liver function were obtained prior to each cycle.Treatment response was assessed biochemically (serum calcitonin and CEA) and by 68Gallium FAPI-PET/CT every 2 cycles. Progression-free survival (PFS) and overall survival (OS) were calculated from first FAPI therapy, with a follow-up duration up to 3 years. Adverse events were graded by CTCAE v5.0. Results Among 14(∼45%) MTC patients receiving tandem 177Lu/225Ac-FAPi dimer therapy, 68% patients had ∼ 52 to 67% decline in serum calcitonin and CEA levels while 17(∼55%) patients who received only 225Ac-FAPi dimer therapy demonstrated 46 to 61 % reduction in serum calcitonin and CEA levels. Restaging 68Ga-FAPi PET/CT in showed partial metabolic responses in 62.5% of patients and stable disease in 20% patients. A median PFS of ∼32 months and median OS of ∼37 months was observed. A substantial percentage of treated patients remained progression-free at 3 years post-therapy, though subsequent PFS data are awaited. Treatment was generally well tolerated with grade III hematologic toxicity observed in few patients in tandem therapy group (anemia in ∼4%, thrombocytopenia in ∼6.5%). Overall, side effects were transient and reversible. The safety profile of 225Ac-FAPI and tandem therapy mostly includes CTCAE v5.0 grade 1–2 effects. Conclusion Our study suggests FAPI RLT as an promising salvage option for advanced MTC. A substantial tumor response rate (by biochemical and PET criteria) and median PFS on the order of 2 to 3 years were observed. The safety profile appears favorable, with few low grade toxicities, mainly hematological. We conclude that tandem 177Lu/225Ac-FAPI or 225Ac-FAPI therapy can achieve encouraging disease control in carefully selected FAP-positive MTC patients, with durable PFS and OS benefits and acceptable toxicity. Citation Format: Dr Nitin Gupta. 225Actinium and tandem 177Lutetium/225Actinium - FAPi therapy in medullary thyroid carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr A013.

The present study aimed to explore the clinical value of color Doppler ultrasound combined with serum tumor markers, including calcitonin (CT) and carcinoembryonic antigen (CEA), for the diagnosis of medullary thyroid carcinoma (MTC). A total of 39 patients with MTC (MTC group), 50 patients with papillary thyroid carcinoma (PTC) (PTC group) and 30 patients with thyroid adenoma (benign control group) were enrolled in the present study. The patients were hospitalized at the Affiliated Hospital of Qingdao University from January 2012 to December 2018 and were diagnosed through surgical procedures and pathology laboratory results. The ultrasound results, as well as serum CT and CEA results, were collected and analyzed. A significant difference was observed between the MTC and PTC groups in regards to morphology, margin, aspect ratio, calcification, internal blood flow and lymph node metastasis (all P<0.01). There was also a significant difference between the MTC and benign control group in regards to internal echo, calcification, internal blood flow and lymph node metastasis (all P<0.01). In addition, the levels of serum CT and CEA in the MTC group were significantly higher than those in the PTC and the benign control groups (both P<0.01). For patients with MTC, the levels of serum CT and CEA were significantly associated with maximum tumor diameter, lymph node metastasis and the patient state after treatment (all P<0.01). Furthermore, the sensitivities of ultrasound, serum CT and CEA for the diagnosis of MTC were 76.92, 74.36 and 68.23%, respectively. The value for the combination of the three markers (94.87%) was significantly higher compared with the sensitivity value of each separate marker (all P<0.05). In conclusion, color Doppler ultrasound combined with detecting the levels of serum tumor markers (CT and CEA) significantly improved the diagnostic efficiency for MTC, which could be useful for the clinical diagnosis and treatment of MTC.

Objective To investigate the value of fine-needle aspiration cytology (FNAC) combined with serum calcitonin in the diagnosis of medullary thyroid carcinoma (MTC). Methods Retrospective analysis of the serum calcitonin and FANC results in 17 cases of MTC confirmed by pathological examination. The diagnostic value of the two methods alone and in combination for MTC were compared. Results 13 of the 17 MTC patients (13/17, 76.5%) underwent fine needle aspiration biopsy before surgery, 11 cases (11/13, 84.6%) diagnosed as thyroid malignant tumor, 7 of whom were diagnosed or suspected of MTC (7/13, 53.8%). Serum calcitonin levels increased in different degrees in 16 patients. The sensitivity of the two methods combined in the diagnosis of MTC was 92.3% (12/13). Conclusions FNAC is an important diagnostic method for the evaluation of thyroid nodules, but it is not sensitive to the diagnosis of MTC. Serum calcitonin is highly sensitive but not universally available. Compared with FNAC alone, FNAC combined with the serum calcitonin examination may significantly improve the detection rate of MTC preoperative and reduce missed diagnosis. Key words: Ultrasonography; Biopsy, fine-needle; Calcitonin; Thyroid neoplasms; Carcinoma, medullary

RET proto-oncogene (RET) mutations were proved to be related to the development of medullary thyroid carcinoma (MTC). We aimed to analyze the role of RET mutations in cervical lymph node metastasis in patients with MTC. Forty-nine patients with preoperatively diagnosed MTC by fine-needle aspiration cytology (FNAC) who underwent bilateral total thyroidectomy with cervical lymphadenectomy were included. Postoperative RET gene test and pathological analysis were performed with the surgical specimens; serum calcitonin (Ctn) and carcinoembryonic antigen (CEA) levels were tested pre- and postoperatively, to evaluate the association between RET mutations and cervical lymph node metastasis in MTC. In these 49 patients, the RET mutation rates of Exon 11, Exon 10, Exon 11&13, Exon 13, and Exon 16 were 20.4%, 4.1%, 38.8%, 22.4%, and 0%, respectively. The lymph node metastasis rates of patients with RET mutation in the central and lateral compartments were 71.4% and 64.3%, respectively, versus 28.6% and 14.3% of patients without RET mutation. The preoperative basal serum levels of Ctn (234.8 ± 188.4 vs. 44.4 ± 27.5, p< 0.01) and postoperative Ctn (49.8 ± 86.4 vs. 3.7 ± 2.2, p= 0.001) in MTC patients with RET mutations were significantly higher than those in MTC patients without RET mutation. In addition, the preoperative (50.2 ± 76.7 vs. 7.4 ± 6.8, p= 0.001) and postoperative serum levels of CEA (13.2 ± 19.5 vs. 1.3 ± 1.6, p< 0.01) in MTC patients with RET mutations were significantly higher than those in MTC patients without RET mutation (p< 0.05). RET mutation was related to cervical lymph node metastasis in patients with MTC, especially the mutation in Exon 11&13. Patients with RET mutation in Exon 11&13 might be regarded as the predictor for prophylactic ipsilateral total cervical lymphadenectomy even without clear evidence of lateral cervical lymph node metastasis.